Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations of the p53 gene are found in hepatocellular carcinoma (HCC), the most common form of primary liver cancer. Specific mutations might reflect exposure to specific carcinogens and we have screened HCC samples from patients in 14 different countries to determine the frequency of a hotspot mutation at codon 249 of the tumour suppressor p53 gene. We detected mutations in 17% of tumours (12/72) from four countries in south Africa and the southeast coast of Asia. There was no codon 249 mutation in 95 specimens of HCC from other geographical locations including North America, Europe, Middle East, and Japan. Worldwide, the presence of the codon 249 mutation in HCCs correlated with high risk of exposure to aflatoxins and the hepatitis B virus (HBV). Further studies were completed in two groups of HBV-infected patients at different risks of exposure to aflatoxins. 53% of patients (8/15) from Mozambique at high risk of aflatoxin exposure had a tumour with a codon 249 mutation, in contrast with 8% of patients from Transkei (1/12) who were at low risk. HCC is an endemic disease in Mozambique and accounts for up to two thirds of all tumours in men. A codon 249 mutation of the p53 gene identifies an endemic form of HCC strongly associated with dietary aflatoxin intake.
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PMID:p53 mutation in hepatocellular carcinoma after aflatoxin exposure. 168 37

Suppressor gene loci involved in the development of hepatocellular carcinoma (HCC) have not been fully identified. The aim of this study was to look for consistent allele loss, or loss of heterozygosity (LOH), in HCC which might represent such gene loci. We have prepared DNA from tumour and non-tumour material from 16 patients with HCC (nine with and seven without liver cirrhosis). Tumour DNA was compared with non-tumour DNA by Southern analysis performed with a panel of 22 probes recognising restriction fragment length polymorphisms assigned to chromosomes 1, 4, 5, 7, 9, 11, 12, 13, 14, 16, 17, 18 and 20. Non-tumour DNA from five of the seven patients with HCC without cirrhosis was heterozygous with the probe Lambda MS8 (5q35-qter), and in all five there was LOH in tumour DNA. Probes for other regions of chromosome 5 have as yet shown no LOH in this group of patients. Cirrhotic HCC patients exhibited LOH on chromosomes 1q and 5p but not in the region 5q35-qter. Both groups of HCC showed LOH on chromosome 17p13. Screening with other probes has not shown any consistent LOH in either group as yet. A comparison of LOH on chromosome 5 in seven patients with colorectal metastasis in the liver showed a different pattern, which suggests that the proposed tumour suppressor gene locus for HCC without cirrhosis on chromosome 5 appears to be distinct from the familial adenomatous polyposis coli gene.
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PMID:Loss of constitutional heterozygosity on chromosome 5q in hepatocellular carcinoma without cirrhosis. 168 7

There are many findings which suggest that an individual may inherit a predisposition for developing a meningioma. The cytogenetics of meningiomas has been well known for some time with monosomy of chromosome 22 as the most characteristic finding. We have confirmed the cytogenetic findings in cultured cells, using molecular genetic techniques on primary tumour tissue. The only difference found between the results of the two techniques was the greater proportion of terminal deletions of the long arm of chromosome 22 detected by the molecular method. The minimal deletion common to 81 meningiomas, and thus the position of the tentative meningioma tumour suppressor gene (TSG), has been determined to lie distal to the myoglobin locus on the long arm of chromosome 22, corresponding to the region 22q12.3-qter. All common histological types of meningioma show the same genetic abnormalities. Study of one tumour with areas of both meningothelial and anaplastic meningioma demonstrated the tumour to be clonal and a partial deletion of 22q to have occurred prior to the development of anaplasia. In order to map in more detail the position of, and finally identify, the TSG involved, a new series of 195 chromosome 22 genomic DNA fragments have been cloned. Current evidence suggests that the genes involved in neurofibromatosis type 2 and meningioma are located at different points on the long arm of chromosome 22 and thus are separate entities.
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PMID:The molecular genetics of meningiomas. 168 96

Point mutations in the p53 gene are the most frequently identified genetic change in human cancer. They convert murine p53 from a tumour suppressor gene into a dominant transforming oncogene able to immortalize primary cells and bring about full transformation in combination with an activated ras gene. In both the human and murine systems the mutations lie in regions of p53 conserved from man to Xenopus. We have developed a monoclonal antibody to p53 designated PAb240 which does not immunoprecipitate wild type p53. A series of different p53 mutants all react more strongly with PAb240 than with PAb246. The PAb240 reactive form of p53 cannot bind to SV40 large T antigen but does bind to HSP70. In contrast, the PAb246 form binds to T antigen but not to HSP70. PAb240 recognizes all forms of p53 when they are denatured. It reacts with all mammalian p53 and chicken p53 in immunoblots. We propose that immunoprecipitation of p53 by PAb240 is diagnostic of mutation in both murine and human systems and suggest that the different point mutations which convert p53 from a recessive to a dominant oncogene exert a common conformational effect on the protein. This conformational change abolishes T antigen binding and promotes self-oligomerization. These results are consistent with a dominant negative model where mutant p53 protein binds to and neutralizes the activity of p53 in the wild type conformation.
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PMID:Activating mutations in p53 produce a common conformational effect. A monoclonal antibody specific for the mutant form. 169 10

The expression of the tumour suppressor gene p53 was analysed in 11 human breast cancer cell lines by immunohistochemistry, immunoprecipitation and cDNA sequencing. We used a panel of anti-p53 monoclonal antibodies for cell staining and found abnormalities in every case. Eight of the cell lines produce a form of p53 which can be immunoprecipitated by the monoclonal antibody PAb240 but not by PAb1620. In the murine system PAb240 only immunoprecipitates mutant p53. We sequenced p53 cDNA directly from four of the PAb240 positive cell lines using asymmetric PCR templates. All four contained missense mutations in p53 RNA, with no detectable expression of the wild type sequence. Different residues were affected in each cell line, but all the mutations changed amino acids conserved from man to Xenopus. These results imply that as in the murine system, the PAb240 antibody reliably detects a wide variety of p53 mutations and that these mutations have a common effect on the structure of p53. Immunohistochemical data suggest that p53 mutation is the commonest genetic alteration so far detected in primary breast cancer.
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PMID:Genetic and immunochemical analysis of mutant p53 in human breast cancer cell lines. 169 91

As yet, few molecular markers are available that are likely to be useful in predicting the metastatic potential of prostate cancer cancer cells. The need for such "progression markers" is indicated by the expectation that more localized cancers (ie stage A-2, B-1,2) will be clinically diagnosed in the near future, owing to improvements in diagnostic techniques (eg transrectal ultrasound) and the screening of population groups at risk (males over 50 years old). Few model systems are available for such studies. Animal models are unsuitable for the isolation of monoclonal antibodies that detect epitopes associated with the progression of prostate cancer. Since few cell lines are available, an approach using primary cancer tissue should be undertaken. For the differential hybridization approach described here, the choice of species presents no difficulty, since many DNA sequences are conserved between species. However, no model system fully represents the human situation. Hence, differential hybridization studies using primary prostate cancer tissue need to be considered. Moreover, the group of genes/proteins with potential relevance for cancer progression (eg oncogenes, tumour suppressor genes, genes encoding cell adhesion molecules or growth factors) has not been studied extensively in prostate cancer. Because of the intrinsic heterogeneity of prostate tumours, the use of pathologically defined tissue sections is imperative for a reliable study. This could be achieved either by in situ techniques (whereby tissue morphology is conserved) or by step sectioning. The difficulties associated with the small amount of material obtained from such sections can be overcome by the use of techniques based on the polymerase chain reaction. Taking these considerations into account, a systematic screening of prostate cancer with probes representing the above mentioned genes should be undertaken.
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PMID:Molecular methods for predicting the metastatic potential of prostate cancer. 172 88

Four chromosomal regions were tested for loss of constitutional heterozygosity in primary tumours from 85 Icelandic breast cancer patients. Loss of heterozygosity and other types of gene rearrangements were observed in 37% of informative cases at the retinoblastoma locus, RB1, on chromosome 13q. Allele losses on chromosome 17 were tested with two polymorphic probes on 17p and two on 17q. Loss of heterozygosity or other types of genetic rearrangement were detected in 43.5% of cases on 17p near the p53 gene and 40.5% on 17q. In our study abnormalities at the RB1 locus and on chromosome 17 frequently occurred together, indicating that the coincident inactivation of more than one tumour suppressor gene may, in some cases, play a part in tumour formation. No significant correlation was found between these losses and clinico-histological parameters. Family history of breast cancer was found to be more common among patients with RB1 deletions and this trend was strengthened in cases where there were deletions at both the RB1 locus and on chromosome 17.
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PMID:Loss of heterozygosity at selective sites on chromosomes 13 and 17 in human breast carcinoma. 174 6

The tumour suppressor gene p53 has been found to be mutated or inactivated at high frequency in several common human tumours. We have examined a series of exocrine pancreatic carcinomas for over-expression of mutant forms of p53 by immunohistochemistry with a panel of specific antibodies. We found immunodetectable p53 in 13 of 22 (60%) frozen pancreatic cancers and seven of 13 pancreatic cell lines. One of the antibodies, CM1, recognises p53 in formalin-fixed, paraffin-embedded archival material and using this reagent we found immunodetectable p53 in 28 of 124 (23%) pancreatic cancers. We have successfully demonstrated the presence of point mutations by direct sequencing of genomic DNA extracted from archival tissue showing CM1 immunoreactivity. We conclude that p53 activation is an important event in human pancreatic tumorigenesis and that the CM1 antibody can detect a proportion of cases of overexpression of mutant p53 in archival pathological material.
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PMID:Abnormalities of the p53 tumour suppressor gene in human pancreatic cancer. 176 70

Tumour development is the consequence of a multistep process involving the activation of oncogenes and loss of tumour suppressor gene function. The study of molecular alterations which accompany carcinogenesis and distinguish the tumour from its normal cellular counterpart, may provide a basis for the in vivo development of drug resistance and facilitate the rational design of anticancer drugs which exploit these differences. In this review we shal discuss some of the effects of carcinogen exposure in relation to how this may influence the response of a tumour to chemotherapy.
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PMID:Carcinogenesis and the response of tumours to anticancer drugs. 176 46

Using the thyroid follicular cell as a model for multi-stage carcinogenesis, we have investigated the role of two potential negative growth regulators ('anti-oncogenes') in epithelial tumour progression--transforming growth factor-beta 1 (TGF beta 1) and p53. Normal follicular cells, as expected, showed marked growth inhibition in response to TGF beta 1. Adenoma cells were equally inhibited. In contrast, spontaneously and SV40-immortalised follicular cell lines showing features of malignant transformation (notably loss of growth factor dependence) had lost all responsiveness to TGF beta 1, accompanied by a partial loss of its receptors. p53 protein was below detectable limits in normal and in adenoma cells but in contrast very high levels were observed in all three transformed lines. In the SV40-immortalised cells, this was expected in view of the known stabilising effect of the viral large T protein. In the spontaneous line we found strong evidence for point mutation of p53, which is known to have the same effect. Both mechanisms result in loss of p53 tumour suppressor function despite increased protein content. We conclude that loss of inhibition by TGF beta and inactivation of p53 are important steps in in vitro immortalisation and/or in vivo tumour progression in human thyroid follicular cells, and speculate that p53 may mediate or be required for the inhibitory signal normally induced by TGF beta 1.
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PMID:Correlated abnormalities of transforming growth factor-beta 1 response and p53 expression in thyroid epithelial cell transformation. 182 Sep 69


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